Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50674, Germany; Institute for Genetics, University of Cologne, Zülpicher Strasse 47a, Cologne 50674, Germany.
Cell. 2014 Mar 13;156(6):1167-1178. doi: 10.1016/j.cell.2014.01.061.
Aging entails a progressive decline in protein homeostasis, which often leads to age-related diseases. The endoplasmic reticulum (ER) is the site of protein synthesis and maturation for secreted and membrane proteins. Correct folding of ER proteins requires covalent attachment of N-linked glycan oligosaccharides. Here, we report that increased synthesis of N-glycan precursors in the hexosamine pathway improves ER protein homeostasis and extends lifespan in C. elegans. Addition of the N-glycan precursor N-acetylglucosamine to the growth medium slows aging in wild-type animals and alleviates pathology of distinct neurotoxic disease models. Our data suggest that reduced aggregation of metastable proteins and lifespan extension depend on enhanced ER-associated protein degradation, proteasomal activity, and autophagy. Evidently, hexosamine pathway activation or N-acetylglucosamine supplementation induces distinct protein quality control mechanisms, which may allow therapeutic intervention against age-related and proteotoxic diseases.
衰老是蛋白质动态平衡逐渐下降的结果，常导致与年龄相关的疾病。内质网（ER）是分泌蛋白和膜蛋白合成和成熟的场所。ER 蛋白的正确折叠需要共价连接 N-连接糖基化寡糖。在这里，我们报告称，己糖胺途径中 N-糖前体合成的增加可改善 ER 蛋白动态平衡并延长秀丽隐杆线虫的寿命。在生长培养基中添加 N-糖前体 N-乙酰葡萄糖胺可减缓野生型动物的衰老并减轻不同神经毒性疾病模型的病理。我们的数据表明，亚稳态蛋白聚集减少和寿命延长依赖于增强的 ER 相关蛋白降解、蛋白酶体活性和自噬。显然，己糖胺途径的激活或 N-乙酰葡萄糖胺的补充会诱导不同的蛋白质质量控制机制，这可能为治疗与年龄相关和蛋白毒性疾病提供了一种干预手段。
